ABSTRACT: The 6th leading cause of cancer deaths worldwide is esophageal cancer, and its incidence is steadily increasing. The vast majority of esophageal cancers arise at the junction between the esophagus and stomach (gastro-esophageal junction, the GEJ). All current surgical methods for standard of care have resulted in high morbidity. The main issue is that the GEJ has a very sophisticated anti-reflux valve that has defied surgical replacement. We plan to create such a replacement using 3D bioprinting, an automated technology to create 3-dimensional tissue constructs, composed of cells and extracellular matrix (ECM). Specific aim 1 is to bioprint a GEJ that approximates the mechanical strength of a native GEJ and incorporates an anti-reflux valve. This will be done by combining decellularized pig GEJ/esophageal ECM hydrogel with human fibroblasts and smooth muscle cells to create the outer GEJ/esophageal layer with the added feature of an anti-reflux valve that we have designed. Specific aim 2 will explore whether programmable-release capsules containing angiogenic factors can be used to guide vascularization in bioprinted constructs. Capsules (?nanocapsules?) coated with a polymer shell containing gold-nanorods will be bioprinted and then ruptured using a laser wavelength specific to the nanorods. Migration of human endothelial cells toward ruptured capsules containing vascular endothelial growth factor (VEGF) will be evaluated and capsules used to guide vascularization of tissue constructs in a precisely defined pattern that provides efficient coverage. Adjustment of droplet size, VEGF concentration, and timing of release will be explored to create vessels of different sizes with the goal of achieving a perfusable tissue construct. This proposal features 3 innovations: 1) the use of bioprinting with decellularized esophageal ECM and human cells to build a GEJ; 2) the design and incorporation of an anti- reflux valve into the GEJ, also using 3D printing; and 3) the use of 3D printed programmable nanocapsules to guide vascularization. The development of a clinically translatable strategy to replace/repair esophageal tissue would have a major impact on the quality of life for patients who require esophageal surgery due to cancer, end-stage benign disease, trauma or congenital defects. In addition, successful execution of our proposal may result in a big step towards solving the vascularization problem in tissue engineering, and may be applicable to restoring vasculature in under-perfused areas in vivo, or after anastomotic ischemia after surgery or organ transplant.